Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation

Abstract

Nutrition profoundly shapes immunity and inflammation across the lifespan of mammals, from pre- and post-natal periods to later life. Emerging insights into diet-microbiota interactions indicate that nutrition has a dominant influence on the composition-and metabolic output-of the intestinal microbiota, which in turn has major consequences for host immunity and inflammation. Here, we discuss recent findings that support the concept that dietary effects on microbiota-derived metabolites potently alter immune responses in health and disease. We discuss how specific dietary components and metabolites can be either pro-inflammatory or anti-inflammatory in a context- and tissue-dependent manner during infection, chronic inflammation, and cancer. Together, these studies emphasize the influence of diet-microbiota crosstalk on immune regulation that will have a significant impact on precision nutrition approaches and therapeutic interventions for managing inflammation, infection, and cancer immunotherapy.

Figure 1.. Dietary impact on chronic inflammatory diseases.

SCFAs, which are fermented from dietary fiber, enhance histone 3 acetylase (H3cAc) activity in the promoter region of FoxP3 locus and therefore promote differentiation of T cells into Treg cells. The G protein-coupled receptor GPR43 is also required for this process. The enhanced Treg cell response protects from T cell transfer colitis. Additionally, indole compounds produced by microbial conversion of dietary amino acids can act through AhR in ILC3s which promotes IL-22-mediated tissue protection. On the other hand, dietary sugars promote neutrophils which exacerbate DSS colitis. Indole compounds can also activate AhR in T cells which leads to the generation of Tregs, resulting in reduced inflammation and improved disease outcomes in EAE. AhR in microglia also plays role in suppression of inflammation in EAE. On the other hand, high amounts of dietary salt promote Th17 cells which contributes to inflammation and therefore exacerbates EAE. Dietary fat exerts proinflammatory effects by increasing epithelial-derived CCL2 which recruits T cells, neutrophils, and other inflammatory cells in the adipose tissue.

Figure 2.. Impact of dietary components on immunity to infection.

Dietary fiber-derived SCFAs promote macrophages against Salmonella Typhimurium and ETEC. In addition to SCFAs, specific fiber types such as inulin fiber elevate the concentrations of bile acids, which promote IL-33 production in epithelial and stromal cells. IL-33 activates ILC2s which can promote eosinophil accumulation and goblet cells, both of which play critical roles in anti-helminth immunity. Dietary sugar reduces the concentrations of SCFAs. Further, dietary sugar promotes F. rodentium which reduces segmented filamentous bacteria. These lead to reduced activity of immune cells including macrophages and Th17 cells. Dietary fat can also suppress Th17 cells. Together, dietary fat and sugar increase susceptibility to several enteric pathogens including Salmonella, ETEC, and Listeria.

Figure 3.. Alterations in diet impact antitumor immunity and cancer immunotherapy.

Dietary fiber promotes anti-PD1 therapy against melanoma which is associated with increased CD4⁺ T cells. On the other hand, inulin fiber promotes hepatic carcinoma which is associated with increased concentrations of bile acids and neutrophils. Dietary fat reduces the concentrations of SCFAs. This results in impairment of dendritic cell recruitment to the gut-associated lymphoid tissue and promotion of tumor progression in a genetic model of intestinal tumorigenesis. Protein-rich diet which is also rich in tryptophan promotes chemotherapy to pancreatic cancer. Mechanistically, 3-IAA, which is produced by microbial conversion of dietary tryptophan, attenuates tumor progression in a neutrophil myeloperoxidase-dependent manner.